Discovery and SAR of novel 4-thiazolyl-2-phenylaminopyrimidines as potent inhibitors of spleen tyrosine kinase (SYK).
A series of SYK inhibitors based on the phenylamino pyrimidine thiazole lead 4 were prepared and evaluated for biological activity. Lead optimization provided compounds with nanomolar K(i)'s against SYK and potent inhibition in mast cell degranulation assays.
Farmer
Luc J
LJ
Department of Medicinal Chemistry, Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA. luc_farmer@vrtx.com
Bemis
Guy
G
Britt
Shawn D
SD
Cochran
John
J
Connors
Martin
M
Harrington
Edmund M
EM
Hoock
Thomas
T
Markland
William
W
Nanthakumar
Suganthini
S
Taslimi
Paul
P
Ter Haar
Ernst
E
Wang
Jian
J
Zhaveri
Darshana
D
Salituro
Francesco G
FG
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008407:Mast Cells / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects; D008968:Molecular Conformation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013154:Spleen / Q000201:enzymology*; D013329:Structure-Activity Relationship; D000072377:Syk Kinase; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat